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PubMed2000

Diminished adenylate cyclase activity and aquaporin 2 expression in acute renal failure rats.

BACKGROUND: The present study was aimed at investigating the changes of aquaporin 2 (AQP2) expression and its underlying mechanisms in ischemic acute renal failure (ARF). METHODS: ARF was induced by clamping the both renal arteries for 60 minutes in rats. Two or seven days later, AQP2 expression and trafficking were determined in the kidney by Western blot analysis and immunohistochemistry. The activity of adenylate cyclase was also measured. RESULTS: The urinary flow rates in ARF-2 and ARF-7 day were significantly increased in association with decreases of urine osmolality. While there was decreased expression of AQP2 in the cortex, outer medulla, and inner medulla in ARF, it was most pronounced in the outer medulla. The AQP2 expression was reduced in the apical membrane-enriched fraction as well the subapical vesicle-enriched fraction in ARF; however, the degree was greater in the former than in the latter. Immunohistochemical study also showed a markedly decreased expression of AQP2 in the collecting duct in ARF. cAMP generation in response to arginine vasopressin (AVP) in the kidney was attenuated in ARF, most prominently in the outer medulla. cAMP generation in the outer medulla in response to forskolin was not affected, but sodium fluoride was significantly blunted in ARF. CONCLUSIONS: The AVP-stimulated adenylate cyclase activity is impaired in ARF, secondary to a defect at the level of the G protein. The expression of AQP2 was reduced as a consequence, which may in part account for urinary concentration defect in ARF.

Acute Kidney Injury↗
PubMed1988

Sequences of the bovine and yeast ADP-ribosylation factor and comparison to other GTP-binding proteins.

The ADP-ribosylation factor (ARF) is a 21-kDa GTP-binding protein that serves as the cofactor in the cholera toxin-catalyzed activation of the stimulatory guanine nucleotide-binding protein of adenylate cyclase (Gs). An oligonucleotide probe based on the partial amino acid sequence was used to clone ARF from a bovine adrenal chromaffin cDNA library. The yeast (Saccharomyces cerevisiae) ARF gene was then cloned from a YCp50 genomic library by cross-species hybridization by using the coding region of the bovine gene. RNA gel blots of poly(A)+ RNA indicate that only one ARF message size (900 and 2000 base pairs) is present in yeast and cows, respectively. Comparison of the cDNA-derived amino acid sequences of ARF to other GTP-binding proteins reveals a structural relationship between ARF and the ras family of proteins. A slightly better structural relationship is detected when ARF is compared to the alpha subunits of the trimeric GTP-binding proteins, including Gs alpha. All of the biochemical characteristics of the purified ARF, including the lack of GTPase activity and the posttranslational myristoylation, are consistent with the derived sequences. Comparison of the ARF sequences to that of the chicken processed pseudogene (CPS-1), previously reported as a ras homologue, reveals that CPS-1 is actually an ARF-derived gene. These results demonstrate that ARF is a GTP-binding protein with structural features of both the ras and the trimeric GTP-binding protein families.

ADP-Ribosylation Factors↗
PubMed1989

Molecular cloning, characterization, and expression of human ADP-ribosylation factors: two guanine nucleotide-dependent activators of cholera toxin.

ADP-ribosylation factors (ARFs) are small guanine nucleotide-binding proteins that enhance the enzymatic activities of cholera toxin. Two ARF cDNAs, ARF1 and ARF3, were cloned from a human cerebellum library. Based on deduced amino acid sequences and patterns of hybridization of cDNA and oligonucleotide probes with mammalian brain poly(A)+ RNA, human ARF1 is the homologue of bovine ARF1. Human ARF3, which differs from bovine ARF1 and bovine ARF2, appears to represent a newly identified third type of ARF. Hybridization patterns of human ARF cDNA and clone-specific oligonucleotides with poly(A)+ RNA are consistent with the presence of at least two, and perhaps four, separate ARF messages in human brain. In vitro translation of ARF1, ARF2, and ARF3 produced proteins that behaved, by SDS/PAGE, similar to a purified soluble brain ARF. Deduced amino acid sequences of human ARF1 and ARF3 contain regions, similar to those in other G proteins, that are believed to be involved in GTP binding and hydrolysis. ARFs also exhibit a modest degree of homology with a bovine phospholipase C. The observations reported here support the conclusion that the ARFs are members of a multigene family of small guanine nucleotide-binding proteins. Definition of the regulation of ARF mRNAs and of function(s) of recombinant ARF proteins will aid in the elucidation of the physiologic role(s) of ARFs.

ADP-Ribosylation Factors↗
PubMed1996

Saccharomyces cerevisiae Gcs1 is an ADP-ribosylation factor GTPase-activating protein.

Movement of material between intracellular compartments takes place through the production of transport vesicles derived from donor membranes. Vesicle budding that results from the interaction of cytoplasmic coat proteins (coatomer and clathrin) with intracellular organelles requires a type of GTP-binding protein termed ADP-ribosylation factor (ARF). The GTPase cycle of ARF proteins that allows the uncoating and fusion of a transport vesicle with a target membrane is mediated by ARF-dependent GTPase-activating proteins (GAPs). A previously identified yeast protein, Gcs1, exhibits structural similarity to a mammalian protein with ARF-GAP activity in vitro. We show herein that the Gcs1 protein also has ARF-GAP activity in vitro using two yeast Arf proteins as substrates. Furthermore, Gcs1 function is needed for the efficient secretion of invertase, as expected for a component of vesicle transport. The in vivo role of Gcs1 as an ARF GAP is substantiated by genetic interactions between mutations in the ARF1/ARF2 redundant pair of yeast ARF genes and a gcs1-null mutation; cells lacking both Gcs1 and Arf1 proteins are markedly impaired for growth compared with cells missing either protein. Moreover, cells with decreased levels of Arf1 or Arf2 protein, and thus with decreased levels of GTP-Arf, are markedly inhibited for growth by increased GCS1 gene dosage, presumably because increased levels of Gcs1 GAP activity further decrease GTP-Arf levels. Thus by both in vitro and in vivo criteria, Gcs1 is a yeast ARF GAP.

ADP-Ribosylation Factor 1↗
PubMed2003

Risk factors for development of acute renal failure after liver transplantation.

BACKGROUND: Acute renal failure (ARF) is a common complication after liver transplantation (LTx). Identification of risk factors may prevent the development and attenuate the impact of ARF on patients outcome after LTX. METHODS: Retrospective analysis of variables in the pre, intra, and postoperative periods of 92 patients submitted to LTx was performed in order to identify risk factors for development of ARF after LTx. ARF was defined as serum creatinine > or = 2.0 mg/dL in the first 30 days after LTx. Univariate and multivariate analysis by logistic regression were performed. RESULTS: ARF group comprised 56 patients (61%). Preoperative serum creatinine was higher in ARF group. During the intraoperative period, ARF group required more blood transfusions, developed more episodes of hypotension and presented longer anesthesia time. In the postoperative period, ARF group presented higher serum bilirubin and more episodes of hypotension. Dialysis was required in 10 patients (11%). The identifled risk factors for development of ARF were: preoperative serum creatinine > 1.0 mg/dL. more than five blood transfusions in the intraoperative period, hypotension during intra and postoperative periods. The identified mortality risk factors were hypotension in the postoperative period and no recovery of renal function after 30 days. CONCLUSIONS: Several factors are involved in the pathogenesis of ARF after LTx and may influence patients outcome and mortality. Pretransplant renal function and hemodynamic conditions in the operative and postoperative periods were identified as risk factors for development of ARF after LTx. Nonrenal function recovery and postoperative hypotension were identified as mortality risk factors after LTx.

Acute Kidney Injury↗
PubMed2004

Maternal and fetal outcomes in HELLP syndrome complicated with acute renal failure.

OBJECTIVE: This study reviews maternal and fetal outcomes in HELLP syndrome complicated with acute renal failure (ARF), and compares clinical and laboratory findings of the cases of HELLP syndrome that did not develop ARF. MATERIALS AND METHODS: All pregnant women with hypertensive disorders admitted or referred to the maternal and fetal unit were recorded into a perinatal database between January 15, 2002 and September 15, 2003. During the study period, out of 615 cases of hypertensive pregnancy, we followed and delivered 347 cases of severe preeclampsia, of them 132 cases were diagnosed as HELLP syndrome. ARF was defined as creatinine level > or =1.2 mg/dL and/or oliguria <400 mL/24 hr. The cases were divided into three groups on the basis of the highest creatinine level recorded during hospitalization: creatinine <1.2 mg/dL, creatinine > or =1.2 to 2.0 mg/dL, and creatinine > or =2.0 mg/dL. Statistical comparisons were performed by Student t test, X2 analysis, and Fisher's Exact test as appropriate. The value of P < .05 was considered significant. RESULTS: ARF developed in 8.9% (n:31) of severe preeclampsia (n:347); of them, 15 (4.3%) cases were nonoliguric, and all had mildly elevated creatinine levels between 1.2 and 1.9 mg/dL. Moderately elevated creatinine levels were 2 to 3.9 mg/dL in 10 cases, and severely elevated creatinine levels were 4 to 8.4 mg/dL in 6 cases, for a total of 16 (4.6%) cases; creatinine levels were > or =2.0 mg/dL (range: 2.0-8.4 mg/dL). HELLP syndrome was the most frequent cause of ARF, 64.5% (n:20/31), and was observed in 15% (n:20) of 132 cases of HELLP syndrome. Fourteen (88%) of 16 cases that had oliguria and creatinine levels > or =2 mg/dL were detected in HELLP syndrome (n:14/132; 10.6%). Major maternal complications in HELLP syndrome with ARF and creatinine level > or =2 mg/dL in the study group were abruptio placentae (42.8%; n:6/14), incisional hematoma (21%; n:3/14), pulmonary edema (14%; n:2/14), cesarean hysterectomy (7%; n: 1/14), and dialysis (50%; n:7/14). There was no maternal mortality. All patients complicated with ARF were discharged without renal impairment. Perinatal mortality was 26.1% in the cases of HELLP syndrome with ARF-creatinine > or =1.2 mg/dL and further increased to 37.5% when creatinine levels were above 2.0 mg/dL, compared with 11.8% in the cases having creatinine <2.0 mg/dL, and the difference was statistically significant (p:.007). CONCLUSIONS: The most contributing factors leading to ARF in HELLP syndrome were abruptio placentae and HELLP syndrome complicated with ARF, particularly, oliguric ARF has relatively higher maternal complications and perinatal mortality.

Acute Kidney Injury↗
PubMed2004

p19ARF determines the balance between normal cell proliferation rate and apoptosis during mammary gland development.

This study demonstrated, for the first time, the following events related to p19(ARF) involvement in mammary gland development: 1) Progesterone appears to regulate p19(ARF) in normal mammary gland during pregnancy. 2) p19(ARF) expression levels increased sixfold during pregnancy, and the protein level plateaus during lactation. 3) During involution, p19(ARF) protein level remained at high levels at 2 and 8 days of involution and then, declined sharply at day 15. Absence of p19(ARF) in mammary epithelial cells leads to two major changes, 1) a delay in the early phase of involution concomitant with downregulation of p21(Cip1) and decrease in apoptosis, and 2) p19(ARF) null cells are immortal in vivo measured by serial transplantion, which is partly attributed to complete absence of p21(Cip1) compared with WT cells. Although, p19(ARF) is dispensable in mammary alveologenesis, as evidenced by normal differentiation in the mammary gland of pregnant p19(ARF) null mice, the upregulation of p19(ARF) by progesterone in the WT cells and the weakness of p21(Cip1) in mammary epithelial cells lacking p19(ARF) strongly suggest that the functional role(s) of p19(ARF) in mammary gland development is critical to sustain normal cell proliferation rate during pregnancy and normal apoptosis in involution possibly through the p53-dependent pathway.

Animals↗
PubMed2000

Treatment-related acute renal failure in the elderly: a hospital-based prospective study.

BACKGROUND: Elderly individuals need a host of diagnostic procedures and therapeutic interventions to take care of ailments. This prospective study was carried out to determine the magnitude of treatment-related acute renal failure (ARF) in the elderly in a hospital setting, to know about pathogenetic factors and to study the factors that could predict an adverse outcome. METHODS: All elderly patients (>60 years) admitted over a 12-month period were screened prospectively throughout their hospital stay for the development of ARF. RESULTS: Of 31860 patients admitted, 4176 (13%) were elderly. Of these 59 (1.4%) developed ARF in the hospital. Nephrotoxic drugs contributed towards development of ARF in 39 (66%), sepsis and hypoperfusion in 27 (45.7%) each, contrast medium in 10 (16.9%) and postoperative ARF occurred in 15 (25.4%) patients. These pathogenetic factors were responsible for ARF in different combinations. Amongst these combination of pathogenetic factors, radiocontrast administration (partial chi(2) 28.1, P<0.0001), surgery (partial chi(2) 14.89, P=0.001), and drugs (partial chi(2) 6. 22, P=0.0126) predicted ARF on their own. Nine patients (15.23%) needed dialytic support. Of 59 patients, 15 (25.4%) died, of those who survived, 38 (86.3%) recovered renal function completely and six (13.6%) partially. Mortality in the elderly with ARF was significantly higher than in those without ARF (25.4 vs 12.5%; chi(2) 8.3, P=0.03). Sepsis (odds ratio 43), oliguria (odds ratio 64), and hypotension (odds ratio 15) were independent predictors of poor patient outcome on logistic regression analysis. CONCLUSION: Incidence of treatment-related ARF in the elderly was 1.4%, with more than one pathogenetic factor playing a role in the development of ARF in the majority. Sepsis, hypotension, and oliguria were the independent predictors of poor patient outcome.

Acute Kidney Injury↗
PubMed1994

Doppler spectrum analysis to diagnose rejection during posttransplant acute renal failure.

During posttransplant acute renal failure (ARF), the diagnosis of allograft rejection constitutes a major problem. We evaluated the value of Doppler ultrasonography in identifying grafts at risk of rejection during ARF. In 184 recipients of a renal allograft, Doppler examinations were performed on the first and fifth postoperative day. Doppler spectra were quantitatively analyzed with a user-written computer program. Doppler findings were not used in clinical decision making. ARF was defined as a diuresis < 400 ml/24 hr and/or the necessity for dialysis. Doppler spectra obtained on the first day after transplantation showed a resistance index (RI) of 0.59 +/- 0.09 in recipients with immediately functioning cadaveric grafts (n = 123), while living related donor grafts (n = 20) showed a lower RI (0.55 +/- 0.07; P < 0.05). Grafts with ARF (n = 41) showed a considerably higher RI (0.67 +/- 0.13; P < 0.05). When grafts with a duration of ARF < or = 4 days (n = 17) were compared with ARF > 4 days (n = 24), RI was not significantly different (0.63 +/- 0.07 vs. 0.68 +/- 0.15; NS). However, the acceleration time of the systolic deflection of the spectrum waveform (Tmax) was shorter in grafts with ARF > 4 days (86 +/- 47 msec vs. 128 +/- 39 msec; P < 0.05). On the fifth day after transplantation, Doppler spectra in grafts with ARF > 4 days (n = 24) showed a Tmax < 90 msec in 9 patients, 8 of whom experienced rejection during ARF (positive predictive value, 8/9 = 89%). In the 15 patients with Tmax > or = 90 msec, only 2 rejections occurred (negative predictive value, 13/15 = 87%). For the RI (> 0.85), positive predictive value was 4/5 = 80% and negative predictive value (RI < or = 0.85) was 13/19 = 68%. In conclusion, a short acceleration time of the Doppler waveform on the first day after transplantation is associated with a longer duration of ARF. Quantitative analysis of Doppler spectra can be helpful in the identification of patients at risk for rejection and in the timing of allograft biopsy during ARF. Persistently short Tmax values on the fifth day after transplantation perform better in identifying grafts at risk of rejection than high RI values.

Acute Kidney Injury↗
PubMed2002

Failure of BCL-2 up-regulation in proximal tubular epithelial cells of donor kidney biopsy specimens is associated with apoptosis and delayed graft function.

SUMMARY: In renal transplantation, postischemic acute renal failure (ARF) develops in more than 20% of patients. We investigated whether tubular epithelial cells obtained from donor kidneys without subsequent ARF express a different pattern of survival genes, compared with cells from kidneys exhibiting ARF. Donor kidney biopsy specimens were obtained before transplantation from eight recipients of cadaveric kidneys with primary graft function (CAD-PF), eight patients with biopsy-proven ARF without rejection (CAD-ARF), and eight recipients of living donor kidneys with primary graft function (LIV). One thousand proximal tubular epithelial cells per biopsy specimen were isolated by laser capture microdissection. Quantitative analysis of apoptosis and the apoptosis regulatory genes Bcl-2, Bcl-xL, and Bax were performed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling staining and real-time PCR, respectively. Primary cultures of human proximal tubular epithelial cells served as calibrator. The number of apoptotic cells was significantly higher in CAD-ARF compared with LIV and CAD-PF (1.5 +/- 1.1% [p < 0.05] vs. 0.3 +/- 0.2% vs. 0.4 +/- 0.2%; mean +/- SD). The apoptosis inhibitors Bcl-2 and Bcl-xL were significantly up-regulated in renal tubular cells of recipients without ARF compared with CAD-ARF. The ratios of Bcl-2/GAPDH normalized to calibrator were as follows: LIV 48 +/- 30, CAD-PF 38 +/- 55, and CAD-ARF 5 +/- 7 (p < 0.05). The corresponding ratios for Bcl-xL were as follows: LIV 6 +/- 6, CAD-PF 5 +/- 3, and CAD-ARF 1 +/- 1 (p < 0.05). No difference in the expression of the proapoptotic Bax could be observed. These data suggest that failure of proximal tubular cells to respond to injury by up-regulation of survival factors from the Bcl-2 family contributes to postischemic ARF in patients after cadaveric renal transplantation.

Apoptosis↗
PubMed2005

Peripheral CD4 T-cell depletion is not sufficient to prevent ischemic acute renal failure.

BACKGROUND: Ischemia reperfusion injury leading to acute renal failure (ARF) and delayed graft function is an important problem in organ transplantation. CD4+ T cells, essential for transplant rejection, may mediate ischemic ARF. We have demonstrated that the caspase-1 mediated production of IL-18 is pathogenic in ischemic ARF in mice. A potential source of IL-18 in ischemic ARF is the CD4+ T cell. We therefore examined the effect CD4+ T cell depletion on the development of ischemic ARF and the activation of IL-18. METHODS: Functional and histological correlates were examined in two groups of mice with ischemic ARF: 1) CD4 T-cell depleted with the antibody GK1.5, and 2) T-cell receptor alpha-chain deficient (TCRalpha -/-) mice. TCRalpha -/- mice lack the alpha chain of the T-cell receptor and therefore lack functional CD4+ and CD8+ T cells. RESULTS: Flow cytometry of lymph nodes and immunohistochemistry of kidneys demonstrated complete depletion of CD4+ T cells in mice with ischemic ARF treated with GK 1.5. CD4+ T-cell depletion did not confer functional (serum creatinine, BUN and FITC-labeled inulin clearance) or histological protection against ischemic ARF. Likewise, TCRalpha -/- mice were not protected against ischemic ARF. Renal caspase-1 activity and IL-18 protein were similar in CD4+ T-cell depleted and wild-type postischemic reperfusion. CONCLUSIONS: Ischemic ARF can occur in the absence of classical T-cell function. The evaluation of other inflammatory mediators (e.g., macrophages or NK cells) as a source of IL-18 and mediator of ischemic ARF warrants further investigation.

Acute Kidney Injury↗
PubMed2003

The roles of auxin response factor domains in auxin-responsive transcription.

Auxin response factors (ARFs) are transcription factors that bind to TGTCTC auxin response elements in promoters of early auxin response genes. ARFs have a conserved N-terminal DNA binding domain (DBD) and in most cases a conserved C-terminal dimerization domain (CTD). The ARF CTD is related in amino acid sequence to motifs III and IV found in Aux/IAA proteins. Just C terminal to the DBD, ARFs contain a nonconserved region referred to as the middle region (MR), which has been proposed to function as a transcriptional repression or activation domain. Results with transfected protoplasts reported here show that ARFs with Q-rich MRs function as activators, whereas most, if not all other ARFs, function as repressors. ARF DBDs alone are sufficient to recruit ARFs to their DNA target sites, and auxin does not influence this recruitment. ARF MRs alone function as activation or repression domains when targeted to reporter genes via a yeast Gal4 DBD, and auxin does not influence the potency of activation or repression. ARF CTDs, along with a Q-rich MR, are required for an auxin response whether the MRs plus CTDs are recruited to a promoter by an ARF DBD or by a Gal4 DBD. The auxin response is mediated by the recruitment of Aux/IAA proteins to promoters that contain a DNA binding protein with a Q-rich MR and an attached CTD.

Arabidopsis Proteins↗
PubMed2005

Incidence and etiology of acute renal failure among ambulatory HIV-infected patients.

BACKGROUND: Acute renal failure (ARF) is a cause of renal dysfunction in human immunodeficiency virus (HIV)-infected patients. Its incidence and causes have not been studied since the introduction of highly active antiretroviral therapy (HAART) in HIV ambulatory patients. METHODS: This is a prospective cohort study of 754 HIV patients, 18 years or older, seen at a university-based infectious disease clinic between 2000 and 2002. ARF was identified using proportional increases in serum creatinine from baseline and by chart review. Clinical conditions were assessed at the time of the ARF event. ARF incidence rates (IR) were calculated by dividing the number of events by person time at risk. To compare patients with and without ARF, t test or chi-square test were used. RESULTS: Patient's mean age was 40 years; 68% were male and 61% were black. One hundred-eleven ARF events occurred in 71 subjects (IR 5.9 per 100 person-years; 95% CI 4.9, 7.1). ARF was more common in men, in those with CD4 cell count <200 cells/mm(3), and HIV RNA levels >10,000 copies/mL. These patients more often had acquired immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), and have received HAART. ARF was mainly community-acquired, due to prerenal causes or acute tubular necrosis, and associated with opportunistic infections and drugs. Liver disease was a cause of ARF in HCV-infected patients. CONCLUSION: ARF is common in ambulatory HIV patients. Immunosuppression, infection, and HCV are important conditions associated with ARF in the post-HAART era.

AIDS-Associated Nephropathy↗
PubMed2005

Acute renal failure independently predicts mortality after myeloablative allogeneic hematopoietic cell transplant.

BACKGROUND: Patients undergoing myeloablative allogeneic hematopoietic cell transplantation (HCT) have a high incidence of acute renal failure (ARF). However, it is unclear if ARF is independently associated with mortality after this procedure. METHODS: We performed meta-analysis of published reports on ARF after myeloablative allogeneic HCT. Four databases (MEDLINE, Cochrane Library, PubMed, Web of Science) and hand searching of conference proceedings were used to identify the studies. ARF was defined as the doubling of serum creatinine occurring within the first 100 days after HCT. The absolute and the relative risks for death after ARF were calculated for every study. The combined relative risk was calculated using the random effects model. Also, multivariate analysis of patient level data was performed on patients from The University of Colorado to establish independent association between ARF and mortality. RESULTS: One thousand two hundred and eleven patients were included in the meta-analysis from the 6 published reports in the literature. The overall incidence of ARF varied from 42% to 84% in these studies. On combining the studies by random-effects model, the relative risk of death after ARF was 2.22 (95%CI 1.38-3.5, P < 0.001). The analysis of patient level data from the University of Colorado demonstrated increasing mortality with worsening grades of ARF. After controlling for various demographic and clinical variables with logistic regression, patients who required dialysis had a 6.8-fold higher association with mortality. CONCLUSION: ARF appears to independently influence mortality after myeloablative allogeneic HCT. Future studies should be aimed at interventions that can reduce the incidence and severity of ARF with this procedure.

Acute Kidney Injury↗
PubMed2005

p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue.

PURPOSE: The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16(INK4A) and p14(ARF). This study addressed the role of p14(ARF) as a potential prognostic marker in this disease. EXPERIMENTAL DESIGN: p14(ARF) protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Cox's proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with p14(ARF) (p16(INK4A), p53, pRb, p21(WAF1/CIP1), E2F-1). RESULTS: On multivariate analysis, p14(ARF) positivity (nucleolar p14(ARF) staining and/or nuclear p14(ARF) staining in >/=30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14(ARF) positivity was cosegregated with positive (>/=1%) p16(INK4A) staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14(ARF) negative and p53 positive (>50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed. CONCLUSIONS: These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14(ARF) protein predicts for improved DFS and OS independent of established prognostic markers.

Carcinoma, Squamous Cell↗
PubMed2005

Differential gender differences in ischemic and nephrotoxic acute renal failure.

BACKGROUND/AIMS: Recent work has shown that female animals are more resistant to ischemic acute renal failure (ARF) than male animals. The mechanism underlying the gender difference is unclear. Moreover, whether the gender difference holds true for ARF induced by other insults is unknown. This study sought to determine the gender differences in ischemic and nephrotoxic ARF. METHODS: Gender differences were tested in two experimental models of ARF. For ischemic ARF, bilateral clamping of renal pedicles was conducted in C57BL/6 and 129/Sv mice followed by reperfusion. For nephrotoxic ARF, cisplatin was administered to the animals. Renal function, tissue damage, animal survival, and renal cell apoptosis were examined. RESULTS: Ischemic ARF was significantly ameliorated in female mice, as shown by lower serum creatinine and blood urea nitrogen (BUN). Female mice also showed better renal histology, less apoptosis and caspase activation, and a much better survival rate than male mice following ischemic insult. On the contrary, female mice were more sensitive to cisplatin-induced ARF. In these animals, BUN increased at day 1 following cisplatin injection, while in males BUN increases were not shown until day 3. Higher levels of serum creatinine were also recorded in female mice. Renal histology showed severer necrotic tubular damage in females, although apoptosis and caspase activation appeared similar in both genders. Consistently, male mice survived better than females in the nephrotoxic model. CONCLUSION: While female mice were resistant to ischemic ARF, they appeared more sensitive to cisplatin-induced ARF. Investigation of the gender differences at the cellular and molecular levels might provide a new area for mechanistic study of ARF.

Acute Kidney Injury↗
PubMed1981

Renal hemodynamics in experimental acute renal failure.

Results from many laboratories, including our own, support the following view of the status of renal blood flow (RBF) in acute renal failure (ARF). During the initiation phase of virtually all forms of experimental ARF, RBF appears to be substantially decreased. The mechanisms for the decrease in RBF vary depending on the model employed. However, we have shown that changes in cardiac output are involved in both HgCl2 and glycerol models of ARF. The degree to which the decreased RBF contributes to the impaired glomerular filtration rate (GFR) characterizing the initial phase of ARF also depends on the particular model that is studied. In terms of the maintenance phase of ARF, out studies show that total RBF is essentially normal in both glycerol and HgCl2 models of ARF. A general consensus exists that RBF is not related to the decreased GFR in the maintenance phase of ARF, regardless of the model of ARF employed. Results from this laboratory suggest, however, that a hemodynamic mechanism may still contribute to the decreased filtration in ARF despite the dissociation between total RBF and GFR. This mechanism may involve an increase in preglomerular resistance, either alone or in association with a decrease in postglomerular resistance. An extensive amount of research has been performed on the renal circulation in ARF over the past two decades. It appears that this research has basically confirmed Ole Munck's impression of the role of renal blood flow in the pathophysiology of ARF.

Acute Kidney Injury↗
PubMed2002

Impact of cardiopulmonary bypass management on postcardiac surgery renal function.

OBJECTIVE: Cardiac surgery on cardiopulmonary bypass (CPB) is associated with postoperative renal dysfunction and up to 4% of patients with normal preoperative renal function develop acute renal failure (ARF) requiring dialysis. According to recent investigations, CPB management is not evidence-based and, thus, current clinical CPB practice may favor renal dysfunction. The purpose of our study was to investigate if postcardiac surgery renal dysfunction is influenced by CPB management. METHODS: We selected three groups of patients with normal preoperative renal function who had been subjected to cardiac surgical procedures on CPB: 44 patients with postoperative ARF requiring hemofiltration/dialysis (ARF group), 51 patients with postoperative renal dysfunction not requiring hemofiltration/dialysis (serum creatinine increase > 0.5 mg/dl within 48 h postsurgery: CREA group), and 48 patients with normal postoperative renal function (Control group). The patients' on-line CPB records were analyzed for CPB duration, CPB perfusion pressure, CPB flow, and periods on CPB at a perfusion pressure <60 mmHg. On-CPB diuretic and vasoconstrictor medication was recorded. RESULTS: Patient demographics were similar for the three groups. In the ARF group, CPB duration was longer (166 +/- 77 [standard deviation, SD] min) compared to CREA (115 +/- 41 min; p < 0.001) and to Control groups (107 +/- 40 min; p < 0.001), and mean CPB flow was lower (2.35 +/- 0.36 l/min/m2) compared to CREA (2.61 +/- 0.35 l/min/m2; p = 0.0015) and to Control groups (2.51 +/- 0.33 l/min/m2; p = 0.09). Mean arterial pressure on CPB (ARF: 61 +/- 10; CREA: 60 +/- 7; CONTROL: 63 +/- 9 mmHg; p = 0.19) as well as furosemide and norepinephrine medication on CPB were similar for the groups. Compared to Control (46 +/- 26 min), CPB duration at arterial pressures <60 mmHg was longer in ARF (78 +/- 60 min; p = 0.034) and in CREA (62 +/- 36 min;p = 0.048). CONCLUSIONS: Our data suggest that current clinical CPB management impacts postoperative renal function. We found that patients with normal preoperative renal function who developed postoperative ARF had longer CPB duration, lower CPB perfusion flow, and longer periods on CPB at pressures < 60 mmHg compared to patients with no post CPB ARF. However, our data do not allow us to separate these CPB-related factors from the potential influence of perioperative low cardiac output syndrome as a cause for postoperative ARF. Thus, future clinical studies are required to elucidate CPB-induced ARF and to optimize CPB management for ARF prevention.

Acute Kidney Injury↗